Objective: To evaluate in a preliminary manner the feasibility, safety, and efficacy of Constraint-Induced Movement therapy (CIMT) of persons with impaired lower extremity use from multiple sclerosis (MS). Design: Clinical trial with periodic follow-up for up to 4 years. Setting: University-based rehabilitation research laboratory. Participants: A referred sample of ambulatory adults with chronic MS (N=4) with at least moderate loss of lower extremity use (average item score ≤6.5/10 on the functional performance measure of the Lower Extremity Motor Activity Log [LE-MAL]). Interventions: CIMT was administered for 52.5 hours over 3 consecutive weeks (15 consecutive weekdays) to each patient. Main Outcome Measures: The primary outcome was the LE-MAL score at posttreatment. Secondary outcomes were posttreatment scores on laboratory assessments of maximal lower extremity movement ability. Results: All the patients improved substantially at posttreatment on the LE-MAL, with smaller improvements on the laboratory motor measures. Scores on the LE-MAL continued to improve for 6 months afterward. By 1 year, patients remained on average at posttreatment levels. At 4 years, half of the patients remained above pretreatment levels. There were no adverse events, and fatigue ratings were not significantly changed by the end of treatment. Conclusions: This initial trial of lower extremity CIMT for MS indicates that the treatment can be safely administered, is well tolerated, and produces substantially improved real-world lower extremity use for as long as 4 years afterward. Further trials are needed to determine the consistency of these findings. © 2013 by the American Congress of Rehabilitation Medicine.